Systemic lupus erythematosus (SLE) is a severe, complex, and clinically heterogeneous autoimmune disease which affects certain populations more severely than others. African-Americans (AA) exhibit a 3-5 fold increased prevalence with more severe manifestations, and greater mortality than individuals of European ancestry. Genetic research in lupus demonstrates that the strength of many genetic associations may also vary between different ethnic populations. There is also evidence that population admixture may play a significant role in influencing the risk of lupus in AA. Our preliminary data on whole-genome admixture scan using 1032 AA cases detected a significant association of SLE risk with elevated European ancestry at 2q22-24 (LOD=6.3, p<3.3x10-8). To identify SLE susceptibility genes within this admixture signal, we performed a candidate gene analysis (284 SNPs from 28 genes) in a follow-up study using 1425 AA cases and 1771 unrelated controls. We have evidence of association (0.05>p>10-6) for 6 novel genes. We have replicated some of these associations in individuals with European (0.05>p>10-5) and Asian (0.05>p>10-3) ancestry. Additionally, some of these associated genes are already reported to be strongly associated with other autoimmune diseases (i.e., Type 1 diabetes) implicating a role of general autoimmunity genes. Taken together, we hypothesize that 2q22-24 is an important and robust SLE susceptibility region which contains multiple, independent SLE predisposing variants, and these will be detected by leveraging differences in local LD structure among ethnically diverse populations. In the current proposal we will follow-up this region with dense fine-mapping and candidate gene analyses to identify SLE susceptibility genes. We will use a large set of individuals (7000 cases and 8000 controls from African, European, Asian, and Amerindian origin) with well-characterized clinical sub-phenotypes (by ACR criteria and autoantibody profiles) from 5 ethnically diverse populations. Our proposed cohort has adequate power to detect common variants with an OR=1.2. Using multiple ethnic populations will not only allow us to detect ethnic-specific or robust association across ethnically-diverse populations, but will also allow for trans-racial mapping to pin-point true predisposing variants and its relative contribution to SLE susceptibility. Upon detecting SLE susceptibility genes we will perform a genotype-phenotype correlation with clinical (ACR) criteria and autoantibody profiles. A detailed analysis of clinical phenotypic variables and their relationship to associated variants may directly address some aspects of clinical heterogeneity of SLE. Together with our research strategies, expertise, experience, track record of our research team, and available biomaterials, resources and infrastructure, we have great potential to successfully detect SLE predisposing variants at 2q22-24 identified through admixture mapping. PUBLIC HEALTH RELEVANCE: Lupus is a severe, debilitating autoimmune disease that represents a significant healthcare burden in the USA and worldwide. We have identified a genomic region in chromosome 2 that may harbor multiple independent SLE susceptibility genes. None of the previously identified lupus genes are from this genomic interval. We will identify the SLE predisposing variants by comparing the genetic variants among multiple populations from diverse ethnicities. This study will not only identify the susceptibility genes but will also shed light on the relative contribution of genes and predisposing variants to the SLE susceptibility in individuals associated with African, European, Asian, and Native-American ancestries.